Solid state forms of palbociclib dimesylate

ABSTRACT

Solid state forms of Palbociclib dimesylate, processes for preparation thereof and use thereof for preparation of Palbociclib are disclosed.

FIELD OF THE DISCLOSURE

The present disclosure encompasses solid state forms of Palbociclibdimesylate, processes for preparation thereof and use thereof forpreparation of Palbociclib.

BACKGROUND OF THE DISCLOSURE

Palbociclib,6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one,has the following chemical structure:

Palbociclib is a kinase inhibitor indicated in combination withletrozole for the treatment of postmenopausal women with estrogenreceptor (ER)-positive, human epidermal growth factor receptor 2(HER2)-negative advanced breast cancer as initial endocrine-basedtherapy for their metastatic disease.

Palbociclib was described in WO 2003/062236. WO 2005/005426 describedcrystalline forms of isethionate, mesylate, dimesylate, HCl and di-HClsalts of Palbociclib. Further crystalline forms and amorphous form ofPalbociclib HCl are described in WO 2016/066420. WO 2016/092442 and WO2016/090257 describe crystalline forms of Palbociclib salts includingphosphate, acetate, lactate, maleate, fumarate, citrate, succinate,L-tartarate, glutarate, adipate, glyconate, diesylate, hippurate,esylate and isethionate.

WO 2014/128588 discusses two crystalline forms, denominated A and B ofPalbociclib.

Polymorphism, the occurrence of different crystalline forms, is aproperty of some molecules and molecular complexes. A single moleculemay give rise to a variety of polymorphs having distinct crystalstructures and physical properties like melting point, thermal behaviors(e.g. measured by thermogravimetric analysis—“TGA”, or differentialscanning calorimetry—“DSC”), X-ray diffraction pattern, infraredabsorption fingerprint, and solid state (¹³C) NMR spectrum. One or moreof these techniques may be used to distinguish different polymorphicforms of a compound.

Different salts and solid state forms (including solvated forms) of anactive pharmaceutical ingredient may possess different properties. Suchvariations in the properties of different salts and solid state formsand solvates may provide a basis for improving formulation, for example,by facilitating better processing or handling characteristics, changingthe dissolution profile in a favorable direction, or improving stability(polymorph as well as chemical stability) and shelf-life. Thesevariations in the properties of different salts and solid state formsmay also offer improvements to the final dosage form, for instance, ifthey serve to improve bioavailability. Different salts and solid stateforms and solvates of an active pharmaceutical ingredient may also giverise to a variety of polymorphs or crystalline forms, which may in turnprovide additional opportunities to assess variations in the propertiesand characteristics of a solid active pharmaceutical ingredient.

Discovering new solid state forms and solvates of a pharmaceuticalproduct may yield materials having desirable processing properties, suchas ease of handling, ease of processing, storage stability, and ease ofpurification or as desirable intermediate crystal forms that facilitateconversion to other polymorphic forms. New solid state forms of apharmaceutically useful compound can also provide an opportunity toimprove the performance characteristics of a pharmaceutical product. Itenlarges the repertoire of materials that a formulation scientist hasavailable for formulation optimization, for example by providing aproduct with different properties, e.g., a different crystal habit,higher crystallinity, or polymorphic stability, which may offer betterprocessing or handling characteristics, improved dissolution profile, orimproved shelf-life (chemical/physical stability). For at least thesereasons, there is a need for additional solid state forms (includingsolvated forms) of Palbociclib.

Processes for preparation of Palbociclib were disclosed in WO2003/062236, WO 2005/005426 and WO 2014/128588. The process developmentof Palbociclib is also discussed in Org. Process Res & Dev. 2016, 20,1191-1202 (Duan et al.), 1203-1216 (Sutherland et al.) and 1217-1226(Chekal et al).

However, Palbociclib obtained by prior art processes may typicallycontain the compound,2-{[5-(1-piperazinyl)-2-pyridinyl]amino}-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one,(herein designated as “Impurity A”) as an impurity which is representedby the following structural formula:

Impurity A is difficult to remove from the desired Palbociclib.

For at least these reasons, there is a need to develop robust processesfor preparation of Palbociclib.

SUMMARY OF THE DISCLOSURE

The present disclosure provides solid state forms of Palbociclibdimesylate, processes for preparation thereof and use thereof forpreparation of Palbociclib, solid state forms thereof, salts thereof andtheir solid state forms.

The present disclosure further provides solid state forms of palbociclibdimesylate for use in the preparation of Palbociclib, solid state formsthereof, salts thereof and their solid state forms.

The present disclosure further provides pharmaceutical compositionscomprising Palbociclib dimesylate and pharmaceutical compositionscomprising Palbociclib prepared by the processes of the presentdisclosure.

The present disclosure provides solid state forms of Palbociclibdimesylate for use in the preparation of pharmaceutical compositions ofPalbociclib and salts thereof.

The present disclosure also encompasses the use of the Palbociclibdimesylate solid state forms of the present disclosure for thepreparation of pharmaceutical compositions of Palbociclib and saltsthereof.

The present disclosure comprises processes for preparing pharmaceuticalcompositions comprising Palbociclib dimesylate. The processes comprisecombining Palbociclib dimesylate solid state forms or with at least onepharmaceutically acceptable excipient.

The present disclosure comprises processes for preparing pharmaceuticalcompositions comprising Palbociclib. The processes comprise combiningPalbociclib prepared by the processes of the present invention with atleast one pharmaceutically acceptable excipient.

The solid state forms and the pharmaceutical compositions of Palbociclibdimesylate of the present disclosure can be used as medicaments,particularly for the treatment of postmenopausal women with estrogenreceptor (ER)-positive, human epidermal growth factor receptor 2(HER2)-negative advanced breast cancer as initial endocrine-basedtherapy for their metastatic disease.

The present disclosure also provides methods of treating postmenopausalwomen with estrogen receptor (ER)-positive, human epidermal growthfactor receptor 2 (HER2)-negative advanced breast cancer as initialendocrine-based therapy for their metastatic disease, comprisingadministering a therapeutically effective amount of a Palbociclibdimesylate solid state form of the present disclosure, or at least oneof the above pharmaceutical compositions, to a subject in need of thetreatment.

Palbociclib prepared by the processes of the present disclosure can beused as medicament, particularly for the treatment of postmenopausalwomen with estrogen receptor (ER)-positive, human epidermal growthfactor receptor 2 (HER2)-negative advanced breast cancer as initialendocrine-based therapy for their metastatic disease.

The present disclosure also provides methods of treating postmenopausalwomen with estrogen receptor (ER)-positive, human epidermal growthfactor receptor 2 (HER2)-negative advanced breast cancer as initialendocrine-based therapy for their metastatic disease, comprisingadministering a therapeutically effective amount of a Palbociclibprepared by the process of the present disclosure, or at least one ofthe above pharmaceutical compositions, to a subject in need of thetreatment.

The present invention also provides the use of the solid state form ofPalbociclib dimesylate of the present invention, or at least one of theabove pharmaceutical compositions or formulations for the manufacture ofa medicament for treating postmenopausal women with estrogen receptor(ER)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced breast cancer as initial endocrine-based therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffractogram (“XRPD”) of Form E ofPalbociclib dimesylate.

FIG. 2 shows a potentiometric titration curve of Form E of Palbociclibdimesylate.

FIG. 3 shows an X-ray powder diffractogram (“XRPD”) of Form F ofPalbociclib dimesylate.

FIG. 4 shows an X-ray powder diffractogram (“XRPD”) of a Form G ofPalbociclib dimesylate.

FIG. 5 shows an FTIR spectrum of Form E of Palbociclib dimesylate.

FIG. 6 shows an FTIR spectrum of Form F of Palbociclib dimesylate.

FIG. 7 shows a solid state ¹³C NMR spectrum of Form E of Palbociclibdimesylate (Full range—200-0 ppm).

FIG. 8 shows a solid state ¹³C NMR spectrum of Form E of Palbociclibdimesylate (zoomed—200-100 ppm).

FIG. 9 shows a solid state ¹³C NMR spectrum of Form F of Palbociclibdimesylate (Full range—200-0 ppm).

FIG. 10 shows a solid state ¹³C NMR spectrum of Form F of Palbociclibdimesylate (zoomed—200-100 ppm).

FIG. 11 shows an X-ray powder diffractogram of form A of Palbociclibfrom WO 2014/128588.

FIG. 12 shows an X-ray powder diffractogram of form A of Palbociclibobtained by example 6.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure provides solid state forms of Palbociclibdimesylate, processes for preparation thereof and use thereof forpreparation of Palbociclib, solid state forms thereof, salts thereof andtheir solid state forms. Solid state properties of Palbociclibdimesylate can be influenced by controlling the conditions under whichthe Palbociclib dimesylate is obtained in solid form.

The products obtained by prior art processes may typically containquantities of the compound,2-{[5-(1-piperazinyl)-2-pyridinyl]amino}-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one,(herein designated as “Impurity A”) as an impurity which is representedby the following structural formula:

The routes for preparation of Palbociclib described in the literatureare summarized in scheme I.

Impurity A is apparently formed due to the presence of impurity A1(represented by the following formula) in tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(designated herein compound II)

IPCOM000244149 discloses preparation of compound 4 containing controlledlevels of impurity A1, that in turn leads to the formation of impurityA. However, Impurity A1 is also formed in the process for formation ofthe enol ether side chain by Heck coupling, i.e. in the formation ofcompound II.

Impurity A is Difficult to Remove from the Desired Product.

Conversion of compound II to palbociclib occurs in aqueous solventmixtures using strong acids. It was surprisingly found that usingmethanesulfonic acid for this conversion leads to the formation ofcrystalline forms of palbociclib dimesylate, that offer significantimpurity purging capability in that level of Impurity A or a saltthereof (particularly Impurity A mesylate or Impurity A dimesylate) inthe solid state forms of palbociclib dimesylate of the presentdisclosure were lower than the levels of Impurity A1 in the compound offormula II before reaction and crystallization.

Further, the process of the present disclosure provides Palbocicliband/or Palbociclib dimesylate in overall high yield, and high quality,i.e. high chemical purity. Specifically, the process of the presentdisclosure provides Palbociclib which contains about 0.1% or less,preferably about 0.08% or less, more preferably 0.05% or less of2-{[5-(1-piperazinyl)-2-pyridinyl]amino}-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-oneherein designated as “impurity A”) as an impurity. Therefore, theprocesses of the present disclosure can be adapted to production in anindustrial scale, i.e., greater than 1 kilogram scale.

A solid state form (or polymorph) may be referred to herein aspolymorphically pure or as substantially free of any other solid state(or polymorphic) forms. As used herein in this context, the expression“substantially free of any other forms” will be understood to mean thatthe solid state form contains 20% or less, 10% or less, 5% or less, 2%or less, or 1% or less of any other forms of the subject compound asmeasured, for example, by PXRD. Thus, solid state of Palbociclibdimesylate described herein as substantially free of any other solidstate forms would be understood to contain greater than 80% (w/w),greater than 90% (w/w), greater than 95% (w/w), greater than 98% (w/w),or greater than 99% (w/w) of the subject solid state form of Palbociclibdimesylate. Accordingly, in some embodiments of the invention, thedescribed solid state forms of Palbociclib dimesylate may contain from1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of one ormore other solid state forms of the same Palbociclib dimesylate.

Depending on which other solid state forms comparison is made, thecrystalline forms of Palbociclib dimesylate of the present disclosurehave advantageous properties selected from at least one of thefollowing: chemical purity, flowability, solubility, dissolution rate,morphology or crystal habit, stability—such as chemical stability aswell as thermal and mechanical stability with respect to polymorphicconversion, stability towards dehydration and/or storage stability, lowcontent of residual solvent, a lower degree of hygroscopicity,flowability, and advantageous processing and handling characteristicssuch as compressibility, and bulk density.

A solid state form, such as a crystal form or amorphous form, may bereferred to herein as being characterized by graphical data “as depictedin” or “as substantially depicted in” a Figure. Such data include, forexample, powder X-ray diffractograms and solid state NMR spectra. As iswell-known in the art, the graphical data potentially providesadditional technical information to further define the respective solidstate form (a so-called “fingerprint”) which cannot necessarily bedescribed by reference to numerical values or peak positions alone. Inany event, the skilled person will understand that such graphicalrepresentations of data may be subject to small variations, e.g., inpeak relative intensities and peak positions due to certain factors suchas, but not limited to, variations in instrument response and variationsin sample concentration and purity, which are well known to the skilledperson. Nonetheless, the skilled person would readily be capable ofcomparing the graphical data in the Figures herein with graphical datagenerated for an unknown crystal form and confirm whether the two setsof graphical data are characterizing the same crystal form or twodifferent crystal forms. A crystal form of palbociclib dimesylatereferred to herein as being characterized by graphical data “as depictedin” or “as substantially depicted in” a Figure will thus be understoodto include any crystal forms of Palbociclib dimesylate characterizedwith the graphical data having such small variations, as are well knownto the skilled person, in comparison with the Figure.

As used herein, and unless stated otherwise, the term “anhydrous” inrelation to crystalline forms of Palbociclib dimesylate relates to acrystalline form of Palbociclib dimesylate which does not include anycrystalline water (or other solvents) in a defined, stoichiometricamount within the crystal. Moreover, an “anhydrous” form would typicallynot contain more than 1% (w/w) of either water or organic solvents asmeasured for example by TGA.

The term “solvate,” as used herein and unless indicated otherwise,refers to a crystal form that incorporates a solvent in the crystalstructure. When the solvent is water, the solvate is often referred toas a “hydrate.” The solvent in a solvate may be present in either astoichiometric or in a non-stoichiometric amount.

As used herein, and unless indicated otherwise, the term “wetcrystalline form” refers to a polymorph that was not dried using anyconventional techniques to remove residual solvent. Examples for suchconventional techniques can be, but not limited to, evaporation, vacuumdrying, oven drying, drying under nitrogen flow etc.

As used herein, and unless indicated otherwise, the term “drycrystalline form” refers to a polymorph that was dried using anyconventional techniques to remove residual solvent. Examples for suchconventional techniques can be, but not limited to, evaporation, vacuumdrying, oven drying, drying under nitrogen flow etc.

As used herein, the term “isolated” in reference to solid state forms ofPalbociclib dimesylate of the present disclosure corresponds to a solidstate form of Palbociclib dimesylate that is physically separated fromthe reaction mixture in which it is formed.

As used herein, unless stated otherwise, PXRD peaks reported herein arepreferably measured using CuK α radiation, λ\, =1.5418 Å. Preferably,PXRD peaks reported herein are measured using CuK α radiation, λ\,=1.5418 Å, at a temperature of 25±3° C. Alternatively, if an instrumentwith a different wavelength is used, for example, when using highresolution XRD method, such as synchrotron, the data may be corrected towavelength of 1.5418 respectively.

As used herein crystalline form A of Palbociclib refers to a crystallineform as described in WO 2014/128588, which may be characterized by X-raypowder diffraction pattern as depicted in FIG. 11.

As used herein, unless stated otherwise, chemical purity (area percent)may be measured by HPLC analysis. Preferably, the HPLC analysis iscarried out using a reversed phase column (e.g. C-18 column) using UVdetection at 290 nm. Any suitable eluent can be used to carry out theseparation (preferably acetonitrile is used). Chemical purity may alsobe measured by wt %.

A thing, e.g., a reaction mixture, may be characterized herein as beingat, or allowed to come to “room temperature” or “ambient temperature”,often abbreviated as “RT.” This means that the temperature of the thingis close to, or the same as, that of the space, e.g., the room or fumehood, in which the thing is located. Typically, room temperature is fromabout 20° C. to about 30° C., or about 22° C. to about 27° C., or about25° C.

The amount of solvent employed in a chemical process, e.g., a reactionor crystallization, may be referred to herein as a number of “volumes”or “vol” or “V.” For example, a material may be referred to as beingsuspended in 10 volumes (or 10 vol or 10V) of a solvent. In thiscontext, this expression would be understood to mean milliliters of thesolvent per gram of the material being suspended, such that suspending a5 grams of a material in 10 volumes of a solvent means that the solventis used in an amount of 10 milliliters of the solvent per gram of thematerial that is being suspended or, in this example, 50 mL of thesolvent. In another context, the term “v/v” may be used to indicate thenumber of volumes of a solvent that are added to a liquid mixture basedon the volume of that mixture. For example, adding solvent X (1.5 v/v)to a 100 ml reaction mixture would indicate that 150 mL of solvent X wasadded.

A process or step may be referred to herein as being carried out“overnight.” This refers to a time interval, e.g., for the process orstep, that spans the time during the night, when that process or stepmay not be actively observed. This time interval is from about 8 toabout 20 hours, or about 10-18 hours, typically about 16 hours.

As used herein, the term “reduced pressure” refers to a pressure that isless than atmospheric pressure. For example, reduced pressure is about10 mbar to about 500 mbar.

The modifier “about” should be considered as disclosing the rangedefined by the absolute values of the two endpoints. For example, theexpression “from about 2 to about 4” also discloses the range “from 2 to4.” When used to modify a single number, the term “about” may refer toplus or minus 10% of the indicated number and includes the indicatednumber. For example, “about 10%” may indicate a range of 9% to 11%, and“about 1” means from 0.9-1.1.

In one embodiment the present disclosure relates to a crystalline formof Palbociclib dimesylate designated form E. The crystalline form E ofPalbociclib dimesylate can be characterized by data selected from one ormore of the following: an XRPD pattern as depicted in FIG. 1; an XRPDpattern having peaks at 9.2, 10.0, 16.4, 18.2 and 21.9 degrees twotheta±0.2 degrees two theta; an FT-IR spectrum substantially as depictedin FIG. 5; an FT-IR spectrum having absorptions at 3385, 1697, 1607,1529, 1332, 913, 857 and 768 cm⁻¹±4 cm⁻¹; a solid state ¹³C NMR spectrumsubstantially as depicted in FIG. 7 or in FIG. 8; a solid state ¹³C NMRspectrum having peaks at 144.5, 143.2, 131.5, 123.5 and 119.2 ppm±0.2ppm; a solid state 13C NMR spectrum having the following chemical shiftabsolute differences between said characteristic peaks at 144.5, 143.2,131.5, 123.5 and 119.2 ppm±0.2 ppm and a reference peak at 110.5 ppm±1ppm of 34.0, 32.7, 21.0, 13.0 and 8.7 ppm±0.1 ppm; and combinations ofthese data.

Crystalline form E of Palbociclib dimesylate may be furthercharacterized by an XRPD pattern having peaks as described above andalso having any one, two, three, four or five additional peaks selectedfrom the group consisting of 6.0, 10.9, 12.7, 15.0 and 15.6 degrees twotheta±0.2 degrees 2-theta±0.2 degrees two theta.

Crystalline form E of Palbociclib dimesylate may be characterized by thedata set forth in the following table.

TABLE 1 X-ray powder diffraction peaks of Form E of Palbociclibdimesylate peak position (degrees two theta ± 0.2 degrees two theta) 5.56.0 9.2 10.0 10.9 12.7 15.0 15.6 16.4 17.5 17.8 18.2 18.4 19.3 20.1 21.321.9 22.1 22.8 23.1 23.8 24.4 24.9 25.6 26.7 27.6 29.1 30.3 31.2 31.632.6 33.1 38.8

Crystalline form E of Palbociclib dimesylate may be characterized byFT-IR spectrum having absorptions at 3385, 2960, 1697, 1652, 1607, 1581,1529, 1500, 1457, 1421, 1379, 1361, 1332, 1302, 1283, 1173, 1119, 1042,993, 973, 936, 913, 893, 857, 846, 827, 802, 779, 768, 750, 730, 677,644, 630, 610, 567, 548, 538, 526 and 460 cm⁻¹±4 cm⁻¹. Crystalline formE of Palbociclib dimesylate may be characterized by FT-IR spectrumhaving absorptions at 3385, 2960, 1697, 1652, 1607, 1581, 1529, 1500,1457, 1421, 1379, 1361, 1332, 1302, 1283, 1173, 1119, 1042, 993, 973,936, 913, 893, 857, 846, 827, 802, 779, 768, 750, 730, 677, 644, 630,610, 567, 548, 538, 526 and 460 cm⁻¹±4 cm⁻¹.

Crystalline form E of Palbociclib dimesylate may be characterized by asolid state 13C NMR spectrum having peaks at 160.2, 159.3, 155.4, 144.5,143.2, 139.6, 131.5, 123.5, 119.2, 110.5, 54.9, 50.2, 44.9, 40.1, 39.2,30.2, 25.0 and 15.4 ppm±0.2 ppm.

Crystalline form E of Palbociclib dimesylate may be characterized byeach of the above characteristics alone/or by all possible combinations,e.g. an XRPD pattern having peaks at 9.2, 10.0, 16.4, 18.2 and 21.9degrees two theta±0.2 degrees two theta and an XRPD pattern as depictedin FIG. 1.

In one embodiment of the present disclosure, form E of Palbociclibdimesylate is isolated.

Crystalline form E of Palbociclib dimesylate may be polymorphicallypure.

In another embodiment the present disclosure relates to a crystallineform of Palbociclib dimesylate designated form F. The crystalline form Fof Palbociclib dimesylate can be characterized by data selected from oneor more of the following: an XRPD pattern as depicted in FIG. 3; an XRPDpattern having peaks at 6.7, 7.4, 9.4, 11.0 and 18.8 degrees twotheta±0.2 degrees two theta; an FT-IR spectrum substantially as depictedin FIG. 6; an FT-IR spectrum having absorptions at 1701, 1655, 1619,1583, 1541, 1210, 1041 and 924 cm-1±4 cm⁻¹; a solid state^(13C) NMRspectrum substantially as depicted in FIG. 9 or in FIG. 10; a solidstate ¹³C NMR spectrum having peaks at 161.6, 141.9, 141.1, 138.7 and133.0 ppm±0.2 ppm; a solid state ¹³C NMR spectrum having the followingchemical shift absolute differences between said characteristic peaks at161.6, 141.9, 141.1, 138.7 and 133.0 ppm±0.2 ppm and a reference peak at110.0 ppm±1 ppm of 51.6, 31.9, 31.1, 28.7 and 23.0 ppm±0.1 ppm; andcombinations of these data.

Crystalline form F of Palbociclib dimesylate may be furthercharacterized by an XRPD pattern having peaks as described above andalso having any one, two, three, four or five additional peaks selectedfrom the group consisting of 8.0, 8.7, 13.5, 16.7 and 17.8 degrees twotheta±0.2 degrees 2-theta±0.2 degrees two theta.

Crystalline form F of Palbociclib dimesylate may be characterized by thedata set forth in the following table.

TABLE 2 X-ray powder diffraction peaks of Form F of Palbociclibdimesylate peak position (degrees two theta ± 0.2 degrees two theta) 3.46.7 7.4 8.0 8.7 9.4 10.1 11.0 13.5 15.0 16.7 17.8 18.3 18.8 20.0 21.423.9 26.5

Crystalline form F of Palbociclib dimesylate may be characterized byFT-IR spectrum having absorptions at 3426, 2955, 2865, 1701, 1655, 1619,1583, 1541, 1512, 1460, 1381, 1355, 1318, 1286, 1275, 1210, 1167, 1117,1041, 949, 924, 893, 848, 801, 777, 741, 719, 678, 641, 625, 612, 553,524, 468 and 455 cm⁻¹±4 cm⁻¹.

Crystalline form F of Palbociclib dimesylate may be characterized by asolid state ¹³C NMR spectrum having peaks at 161.6, 155.2, 141.9, 141.1,140.0, 138.7, 135.7, 134.1, 133.0, 120.7, 110.0, 109.4, 54.8, 54.0,53.4, 42.8, 41.5, 40.0, 39.6, 31.8, 30.9, 28.8, 26.6, 25.6, 15.0, 13.8and 12.6 ppm±0.2 ppm

Crystalline form F of Palbociclib dimesylate may be characterized byeach of the above characteristics alone/or by all possible combinations,e.g. an XRPD pattern having peaks at 6.7, 7.4, 9.4, 11.0 and 18.8degrees two theta±0.2 degrees two theta and an XRPD pattern as depictedin FIG. 3.

In one embodiment of the present disclosure, form F of Palbociclibdimesylate is isolated.

Crystalline form F of Palbociclib dimesylate may be polymorphicallypure.

In another embodiment the present disclosure relates to a form ofPalbociclib dimesylate designated form G. The crystalline form G ofPalbociclib dimesylate can be characterized by data selected from one ormore of the following: an XRPD pattern as depicted in FIG. 4; an XRPDpattern having peaks at 6.3, 7.2, 8.6, 9.3, 14.6, 16.4, 17.7 and 18.8degrees two theta±0.2 degrees two theta, and combinations of these data.

In one embodiment of the present disclosure, form G of Palbociclibdimesylate is isolated.

Form G of Palbociclib dimesylate may be polymorphically pure.

The present invention encompasses processes for preparing Palbociclib,Palbociclib salts and their solid state forms. The process comprisespreparing the crystalline forms of palbociclib dimesylate of the presentdisclosure and converting to Palbociclib, palbociclib salts and theirsolid state forms.

The conversion can be done, for example, by a process comprisingbasifying the crystalline forms of Palbociclib dimesylate of the presentdisclosure to obtain Palbociclib and optionally reacting the obtainedPalbociclib base with an appropriate acid, to obtain the correspondingsalt. Alternatively, palbociclib salts may be prepared by saltswitching, i.e., reacting the solid state forms of palbociclibdimesylate of the present disclosure with an acid having a pKa which islower than the pKa of methanesulfonic acid, to obtain the correspondingsalt.

It was surprisingly found that the solid state forms of palbociclibdimesylate of the present disclosure offer significant impurity purgingcapability in that level of Impurity A A, or a salt thereof (inparticular Impurity A mesylate or Impurity A dimesylate) in the solidstate forms of palbociclib dimesylate of the present disclosure werelower than the levels of Impurity A1 in the compound of formula IIbefore reaction and crystallization.

In one embodiment the solid state forms of palbociclib dimesylate of thepresent invention may contain about 0.2% area percent or less,preferably 0.1% area percent or less, more preferably about 0.08% areapercent or less, particularly 0.04% area percent or less of Impurity Aor a salt thereof (in particular, Impurity A mesylate or Impurity Adimesylate), as measured by HPLC. The solid state forms of Palbociclibdimesylate produced by the process according to any aspect or embodimentof the present invention may alternatively contain: ≤1 wt %, ≤0.8 wt %,≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt % (preferably≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1 wt % or≤0.05 wt %) of Impurity A or a salt thereof (in particular, Impurity Amesylate or Impurity A dimesylate) discussed above.

In another embodiment the solid state forms of Palbociclib dimesylate ofthe present invention may have a total impurity content of: not morethan 0.4% area percent, preferably not more than 0.3% area percent, morepreferably not more than 0.2% area percent, and particularly not morethan 0.1% area percent, as measured by HPLC. The solid state forms ofPalbociclib dimesylate according to any aspect or embodiment of thepresent invention may alternatively contain: ≤0.5 wt %, ≤0.25 wt %, ≤0.2wt %, ≤0.1 wt % or ≤0.05 wt % (preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05wt %, and more preferably ≤0.1 wt % or ≤0.05 wt %) of total impurities.

Therefore the solid state forms of palbociclib dimesylate of the presentdisclosure may be used as intermediates in the preparation ofPalbociclib, preferably containing about 0.2% area percent or less,preferably 0.1% area percent or less, more preferably about 0.08% areapercent or less, particularly 0.04% area percent or less of Impurity A,as measured by HPLC. Alternatively, the solid state forms of palbociclibdimesylate of the present disclosure may be used as intermediates in thepreparation of Palbociclib, preferably containing ≤1 wt %, ≤0.8 wt %,≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt % (preferably≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1 wt % or≤0.05 wt %) of Impurity A.

Further, the solid state forms of palbociclib dimesylate of the presentdisclosure may be used as intermediates in the preparation ofPalbociclib, preferably containing about 0.4% area percent or less,preferably 0.3% area percent or less, more preferably about 0.2% areapercent or less, particularly 0.1% area percent or less of totalimpurities, as measured by HPLC. Alternatively, the solid state forms ofpalbociclib dimesylate of the present disclosure may be used asintermediates in the preparation of Palbociclib, preferably containing≤1 wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05wt % (preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably≤0.1 wt % or ≤0.05 wt %) of total impurities.

The present disclosure provides the solid state forms of Palbociclibdimesylate for use for the preparation of palbociclib, preferably withthe above discussed purity characteristics.

Palbociclib produced by the process of the present disclosure maypreferably contain about 0.2% area percent or less, preferably 0.1% areapercent or less, more preferably about 0.08% area percent or less,particularly 0.04% area percent or less of Impurity A. Alternatively,Palbociclib produced by the process of the present disclosure preferablycontains ≤1 wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt %or ≤0.05 wt % (preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and morepreferably ≤0.1 wt % or ≤0.05 wt %) of Impurity A discussed above.

Palbociclib produced by the process of the present disclosure maypreferably contain about 0.4% area percent or less, preferably 0.3% areapercent or less, more preferably about 0.2% area percent or less,particularly 0.1% area percent or less of total impurities.Alternatively, Palbociclib produced by the process of the presentdisclosure may preferably contain ≤1 wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt % (preferably ≤0.2 wt %, ≤0.1 wt% or ≤0.05 wt %, and more preferably ≤0.1 wt % or ≤0.05 wt %) of totalimpurities.

In some embodiments, the solid state forms of Palbociclib dimesylate ofthe disclosure are substantially free of any other forms of Palbociclibdimesylate, or of specified polymorphic forms of Palbociclib dimesylate,respectively.

In another aspect the disclosure relates to processes for preparation ofPalbociclib. The processes of the present invention can be illustratedby the following Scheme 2:

In another aspect the disclosure provides processes for preparing solidstate forms of palbociclib dimesylate, preferably crystalline forms E, Fand G of Palbociclib dimesylate, more preferably wherein the content ofImpurity A or a salt thereof (in particular, Impurity A mesylate orImpurity A dimesylate) is 0.2% area percent or less, preferably 0.1%area percent or less, more preferably 0.08% area percent or less,particularly 0.04% area percent or less of Impurity A or a salt thereof(in particular, Impurity A mesylate or Impurity A dimesylate) discussedabove comprising crystallizing palbociclib dimesylate from a mixture ofwater and acetone.

Alternatively, the disclosure provides processes for preparing solidstate forms of palbociclib dimesylate, preferably crystalline forms E, Fand G, more preferably wherein the content of total impurities is 0.4%area percent or less, preferably 0.3% area percent or less, morepreferably 0.2% area percent or less, particularly 0.1% area percent orless comprising crystallizing palbociclib dimesylate from a mixture ofwater and acetone.

All of the discussed solid state forms of palbociclib dimesylate may beconverted to palbociclib, solid state forms thereof, palbociclib saltsand solid state forms of the salts.

In another aspect the disclosure relates to solid state forms ofpalbociclib dimesylate produced by the processes of the presentdisclosure.

In another aspect the disclosure relates to a process for preparation ofPalbociclib, preferably wherein the content of Impurity A is 0.2% areapercent or less preferably 0.1% area percent or less, more preferably0.08% area percent or less, particularly 0.04% area percent or less ofImpurity A, as measured by HPLC or wherein the content of impurity A is≤1 wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05wt % (preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably≤0.1 wt % or ≤0.05 wt %), or wherein the palbociclib contains ≤1 wt %,≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %(preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1wt % or ≤0.05 wt % of total impurities, which process comprises a)providing the solid state forms of Palbociclib dimesylate of the presentdisclosure; b) converting palbociclib dimesylate to palbociclib; c)separating the solid palbociclib formed; and d) optionally washingand/or drying

Preferably step b of the process may comprise adding a base, preferablyNaOH.

In another aspect the disclosure relates to a process for preparation ofPalbociclib, preferably wherein the content of Impurity A is 0.2% areapercent or less preferably 0.1% area percent or less, more preferably0.08% area percent or less, particularly 0.04% area percent or less ofImpurity A discussed above as measured by HPLC or wherein the content ofimpurity A is ≤1 wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1wt % or ≤0.05 wt % (preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, andmore preferably ≤0.1 wt % or ≤0.05 wt %), or wherein the palbociclibcontains ≤1 wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt %or ≤0.05 wt % (preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and morepreferably ≤0.1 wt % or ≤0.05 wt % of total impurities, which processcomprises a) providing a solution of the state forms of Palbociclibdimesylate of the present disclosure in one or more solvents; b)converting palbociclib dimesylate to palbociclib; c) separating thesolid palbociclib formed; and d) optionally washing and/or drying.

Preferably step a is performed in the presence of a polar protic solventor a polar aprotic solvent or a mixture thereof, preferably water andacetone.

Preferably step b of the process comprises adding a suitable base.Suitable base may include inorganic and organic bases. Examples ofsuitable bases include but are not limited to NaOH, ammonia, sodiumcarbonate, amines, potassium carbonate, sodium bicarbonate. Preferablythe base is NaOH.

In another aspect the disclosure provides a process for preparation ofpalbociclib preferably wherein the content of Impurity A is 0.2% areapercent or less preferably 0.1% area percent or less, more preferably0.08% area percent or less, particularly 0.04% area percent or less ofImpurity A as measured by HPLC or wherein the content of impurity A is≤1 wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05wt % (preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably≤0.1 wt % or ≤0.05 wt %), or wherein the palbociclib contains ≤1 wt %,≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %(preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1wt % or ≤0.05 wt % of total impurities, comprising:

a) providing palbociclib dimesylate or solid state forms of palbociclibdimesylate of the present disclosure in a solvent system comprising apolar protic solvent or a polar aprotic solvent or a mixture thereof,preferably the solvent system comprises water and acetone and optionallystirring until dissolution;

b) adding a base, preferably NaOH, to adjust the pH to a value of fromabout 8 to about 14, preferably pH is adjusted to a value of about 12;

c) optionally separating the solid formed;

d) optionally washing and/or optionally drying to obtain palbociclib.

Preferably, in any of the processes described herein, the water toacetone ratio is from: about 1:1 to about 10:1, about 1:1 to about 5:1,about 1.2:1 to about 3:1 or about 1.4:1 to about 2:1, by volume.

In another aspect the disclosure relates to a process for preparation ofPalbociclib, preferably wherein the content of Impurity A is 0.2% areapercent or less, preferably 0.1% area percent or less, more preferably0.08% area percent or less, particularly 0.04% area percent or less asmeasured by HPLC or wherein the content of impurity A is ≤1 wt %, ≤0.8wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %(preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1wt % or ≤0.05 wt %) or wherein the palbociclib contains ≤1 wt %, ≤0.8 wt%, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt % (preferably≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1 wt % or≤0.05 wt % of total impurities, which process comprises:

a) providing tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(compound II) and methanesulfonic acid in a solvent system comprisingone or more polar solvents, preferably the solvent system compriseswater, and heating the reaction mixture to a temperature of from about25° C. to about the reflux temperature of the solvent system;Alternatively, methanesulfonic acid may be added to compound II in thesolvent system after heating the reaction mixture to a temperature offrom about 25° C. to about the reflux temperature of the solvent system;

b) cooling the reaction mixture to a temperature lower than thetemperature of step a but not less than about 0° C.;

c) optionally filtering;

d) adding a suitable anti solvent to afford a suspension;

e) cooling the suspension to a temperature of about 25° C. to about(−15) ° C.;

f) filtering and optionally washing with the anti solvent used in step dto isolate palbociclib dimesylate; and

g) converting palbociclib dimesylate to palbociclib.

Preferably the solvent system in step a) comprises water and thereaction mixture is heated to a temp of about 80° C. and in step b) thereaction mixture is cooled to a temp of about 50° C.

In a specific embodiment the solvent system in step a) consistsessentially of water.

Suitable anti solvents for step d) of the above process, may include butare not limited to ketones, preferably a C₃-C₈ ketone, such as acetone,methyl ethyl ketone, diethyl ketone etc., ester solvents such as ethylacetate, isopropyl acetate, butyl acetate etc. and alcohol solvents,preferably a C₁-C₆ alcohols, such as methanol, ethanol, propanol,isopropanol, etc.

Preferably the amount of anti-solvent added should afford a solventmixture wherein the amount of the anti-solvent is at least about 4volumes of anti solvent per one volume of solvent.

Preferably the anti solvent is ketone, preferably a C3-C8 ketone, ormore preferably acetone.

In a particular embodiment the anti-solvent is acetone and the solventmixture in step d consists essentially of acetone and water wherein atleast about 4 volumes per one volume of water.

Preferably in step e the reaction mixture is cooled to about (−3) ° C.

In another aspect the disclosure relates to a further process forpreparation of Palbociclib, preferably wherein the content of Impurity Ais 0.2% area percent or less, preferably 0.1% area percent or less, morepreferably 0.08% area percent or less, particularly 0.04% area percentor less as measured by HPLC or wherein the content of impurity A is ≤1wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt% (preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably≤0.1 wt % or ≤0.05 wt %) or wherein the contains ≤1 wt %, ≤0.8 wt %,≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt % (preferably≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1 wt % or≤0.05 wt % of total impurities, which process comprises:

a) providing tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(compound II) and methanesulfonic acid in a solvent system comprisingone or more polar solvents, preferably the solvent system compriseswater, and heating the reaction mixture to a temperature of from about25° C. to about the reflux temperature of the solvent system;

or

providing tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(compound II) in a solvent system comprising one or more polar solvents,preferably the solvent system comprises water, and heating the reactionmixture to a temperature of from about 25° C. to about the refluxtemperature of the solvent and adding methanesulfonic acid;

b) optionally cooling the reaction mixture to a temperature lower thanthe temperature of step a but not less than about 0° C.;

c) optionally filtering;

d) adding a suitable anti solvent at a temperature of about 25° C. toabout reflux temperature, preferably at a temp of about 50° C.;

e) optionally heating to reflux temperature;

f) cooling the reaction mixture to a temperature of about 25° C. toabout (−15) ° C.;

g) separating the solid palbociclib dimesylate and optionally washingwith the anti solvent used in step d); and

h) converting palbociclib dimesylate to palbociclib.

Preferably the reaction mixture in step a) is heated to a temperature ofabout 80° C.

Steps b) and c) may be interchangeable, i.e. the optional cooling stepmay be performed before or after the optional filtering.

In a specific embodiment the solvent system in step a) consistsessentially of water.

Suitable anti solvents for step d) of the above process, may include butare not limited to ketones, preferably a C₃-C₈ ketone, such as acetone,methyl ethyl ketone, diethyl ketone etc., ester solvents such as ethylacetate, isopropyl acetate, butyl acetate etc. and alcohol solvents,preferably a C₁-C₆ alcohol, such as methanol, ethanol, propanol,isopropanol, etc.

Preferably the amount of anti solvent added is such to result in asolvent mixture wherein the ratio of anti-solvent to solvent is at leastabout 4:1 (v/v). Preferably the anti solvent is acetone

In a particular embodiment the anti solvent is acetone and the solventmixture in step d consists essentially of acetone and water preferablyin a ratio of at least about 4 volumes per one volume of water.

Preferably in step f) the reaction mixture is cooled to about (−5) ° C.

In another aspect the disclosure relates to a process for preparation ofPalbociclib, preferably wherein the content of Impurity A is 0.1% orless, 0.08% or less, more preferably 0.05% or less which processcomprises:

a) providing tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(compound II) in acetone and heating to a temperature of about 0° C. toabout the reflux temperature, preferably to about 50° C.;

b) adding a solution of methanesulfonic acid in water;

c) keeping the suspension at a temperature of about 40° C. to about thereflux temperature preferably at about 50° C. to afford a cloudysolution;

d) cooling the reaction mixture to a temperature of about 0° C. to about50° C., preferably to about 25° C.;

e) adding acetone and stirring;

f) filtering and optionally washing with the acetone to isolatepalbociclib dimesylate; and

g) converting palbociclib dimesylate to palbociclib.

Preferably the amount of acetone added in step d) should afford asolvent mixture wherein the amount of the acetone is at least about 4volumes of per one volume of water.

In another aspect the disclosure relates to a further process forpreparation of Palbociclib, preferably wherein the content of Impurity Ais 0.2% area percent or less, preferably 0.1% area percent or less, morepreferably 0.08% area percent or less, particularly 0.04% area percentor less as measured by HPLC or wherein the content of impurity A is ≤1wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt% (preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably≤0.1 wt % or ≤0.05 wt %) or wherein the palbociclib contains ≤1 wt %,≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %(preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1wt % or ≤0.05 wt % of total impurities, which process comprises:

a) providing tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(compound II) in a solvent system comprising water, and heating thereaction mixture to a temperature of about 80° C.;

b) adding methanesulfonic acid

c) optionally cooling the reaction mixture to a temperature lower thanthe temperature of step a but not less than about 0° C., preferably toabout 50° C.;

d) optionally filtering;

e) adding acetone at a temperature of about 25° C. to about refluxtemperature, preferably at a temp of about 50° C.;

f) optionally heating to reflux temperature to get a solution;

g) cooling the reaction mixture to a temperature of about 25° C. toabout (−15) ° C., more preferably about 0° C. to about (−10) ° C.;

h) separating the solid palbociclib dimesylate and optionally washingwith acetone; and

i) converting palbociclib dimesylate to palbociclib.

In a specific embodiment the solvent system in step a) consistsessentially of water.

Steps c) and d) may be interchangeable, i.e. the optional cooling stepmay be performed before or after the optional filtering.

In a particular embodiment the solvent mixture in step e) consistsessentially of acetone and water wherein the ratio of acetone to wateris at least about 4 volumes of acetone per one volume of water.

Preferably in step g the reaction mixture is cooled to about (−5) ° C.

In a particular embodiment, the conversion of palbociclib dimesylate topalbociclib comprises the following steps:

-   -   A) providing palbociclib mesylate in a solvent system comprising        a polar protic solvent or a polar aprotic solvent or a mixture        thereof, preferably wherein the solvent system comprises water        and acetone and optionally stirring until dissolution;    -   B) adding a base, preferably NaOH, to adjust the pH to about 8        to about 14, preferably about 12;    -   C) separating the solid palbociclib formed and optionally        washing; and    -   D) optionally drying.

Preferably, in any of the processes described herein, the water toacetone ratio is from: about 1:1 to about 10:1, about 1:1 to about 5:1,about 1.2:1 to about 3:1 or about 1.4:1 to about 2:1, by volume.

The above solid state forms can be used to prepare other solid stateforms of Palbociclib, palbociclib salts, and their solid state forms.

The present disclosure also provides solid state forms of Palbociclibdimesylate for use in the preparation of pharmaceutical compositions ofPalbociclib and Palbociclib dimesylate.

The present disclosure further provides pharmaceutical compositionscomprising Palbociclib dimesylate and pharmaceutical compositionscomprising Palbociclib prepared by the processes of the presentdisclosure.

The present disclosure provides solid state forms of Palbociclibdimesylate for use in the preparation of pharmaceutical compositions ofPalbociclib and salts thereof.

The present disclosure also encompasses the use of the Palbociclibdimesylate solid state forms of the present disclosure for thepreparation of pharmaceutical compositions of Palbociclib and saltsthereof.

The present disclosure comprises processes for preparing pharmaceuticalcompositions comprising Palbociclib dimesylate. The processes comprisecombining Palbociclib dimesylate solid state forms or with at least onepharmaceutically acceptable excipient.

The present disclosure comprises processes for preparing pharmaceuticalcompositions comprising Palbociclib. The processes comprise combiningPalbociclib prepared by the processes of the present invention with atleast one pharmaceutically acceptable excipient.

The solid state forms and the pharmaceutical compositions of Palbociclibdimesylate of the present disclosure can be used as medicaments,particularly for the treatment of postmenopausal women with estrogenreceptor (ER)-positive, human epidermal growth factor receptor 2(HER2)-negative advanced breast cancer as initial endocrine-basedtherapy for their metastatic disease.

The present disclosure also provides methods of treating postmenopausalwomen with estrogen receptor (ER)-positive, human epidermal growthfactor receptor 2 (HER2)-negative advanced breast cancer as initialendocrine-based therapy for their metastatic disease, comprisingadministering a therapeutically effective amount of a Palbociclibdimesylate solid state form of the present disclosure, or at least oneof the above pharmaceutical compositions, to a subject in need of thetreatment.

Palbociclib prepared by the processes of the present disclosure can beused as medicament, particularly for the treatment of postmenopausalwomen with estrogen receptor (ER)-positive, human epidermal growthfactor receptor 2 (HER2)-negative advanced breast cancer as initialendocrine-based therapy for their metastatic disease.

The present disclosure also provides methods of treating postmenopausalwomen with estrogen receptor (ER)-positive, human epidermal growthfactor receptor 2 (HER2)-negative advanced breast cancer as initialendocrine-based therapy for their metastatic disease, comprisingadministering a therapeutically effective amount of a Palbociclibprepared by the process of the present disclosure, or at least one ofthe above pharmaceutical compositions, to a subject in need of thetreatment.

The present invention also provides the use of the solid state form ofPalbociclib dimesylate of the present invention, or at least one of theabove pharmaceutical compositions or formulations for the manufacture ofa medicament for treating postmenopausal women with estrogen receptor(ER)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced breast cancer as initial endocrine-based therapy. X-ray PowderDiffraction (“XRPD”) method

Sample after being powdered in a mortar and pestle is applied directlyon a silicon plate holder. The X-ray powder diffraction pattern wasmeasured with Philips X'Pert PRO X-ray powder diffractometer, equippedwith Cu irradiation source=1.54184

(

ngström), X'Celerator (2.022° 20) detector.

Scanning parameters: angle range: 3-40 degrees 2-theta, step size0.0167, time per step 37 s, continuous scan.

Measurement Parameters:

Scan range 3-40 degrees 2-theta Scan mode continuous Step size 0.0167degrees Time per step 37 s

Nuclear Magnetic Resonance (NMR) Method

¹H (400 MHz) NMR spectra were recorded on Bruker Avance AV400 NMRspectrometer. D20 and DMSO were used as solvents. Chemical shifts (δ),in ppm, are referred to TMS as internal standard.

Potentiometric Titration Method

Potentiometric titration was performed on a Mettler Toledo DL 53Instrument.

Materials: Titrant: 0.1 N Sodium Hydroxide (NaOH) Probe: DG111

Solvent: Water/Tetrahydrofuran 60:40 (v/v)

Sample Preparation and Procedure:

About 400 mg of accurately weighed palbociclib dimesylate were dissolvedin 60 mL of Solvent and sonicated until complete dissolution.

Potentiometric titration was carried out using 0.1N NaOH and the volumeadded at the second point of inflexion was recorded.

Calculation:

${\% \mspace{14mu} {Methanesulfonic}\mspace{14mu} {Acid}} = {\frac{( {V_{SA} - V_{B}} ) \times 0.1 \times F \times 96.10}{W} \times 100}$

VSA=mL of 0.1N NaOH used in Sample titration;VB=mL of 0.1N NaOH used in Blank titration;F=0.1N NaOH factor;96.10=Methanesulfonic acid molecular weight;W=Sample weight in mg.

HPLC Method Chromatographic Conditions

Column & packing: L-1, C-18, 150*4.6 mm*3.0 μmBuffer: potassium phosphate monobasic about 15 mM, adjust pH 2.1±0.1with 85%orthophosphoric acid solution

Eluent A: Buffer, Eluent B: ACN

Flow: 1.5 mL/min, Detector: 290 nm

Gradient; Time: % Eluent B, (0-10, 16-40, 23-65, 30-65, 32-10)

Retention time peak of Palbociclib: about 6.7 min

FT-IR Spectroscopy Method

IR spectra were recorded on Nicolet 380 spectrometer equipped with KBrbeam splitter and DTGS KBr detector, using ATR technique with ZnSecrystal.

Measurement Parameters:

Spectral range: 4000-400 cm⁻¹Resolution: 4.0 cm⁻¹Number of scans: 128Sample gain: 8

¹³C Solid-State NMR Method

¹³C CP/MAS NMR spectra were measured at 125 MHz using Bruker Avance IIIHD 500 WB/US NMR spectrometer (Karlsruhe, Germany, 2013) at magic anglespinning (MAS) frequency ω_(r)/2π=11 kHz. In all cases finely powderedsamples were placed into 4-mm ZrO2 rotors and the standard “cpmas”pulseprogram was used. During acquisition of the data the high-powerdipolar decoupling SPINAL 64 was applied. The flip-pulse length was 4.8μs. Applied nutation frequency of B1(¹H) field was ω_(l)/2π=89.3 kHz.Nutation frequency of B1(¹³C) and B1(¹H) fields duringcross-polarization was ω_(l)/2π=62.5 kHz. The cross-polarization contacttime was 2 ms. The ¹³C scale was calibrated with glycine as externalstandard (176.03 ppm—low-field carbonyl signal). Experimental details(key parameters such as repetition delay, D1, and number of scans, NS)for each of the measured samples are listed in Table 3.

The NMR spectrometer was completely calibrated and all experimentalparameters were carefully optimized prior the investigation of samples.Magic angle was set using KBr during standard optimization procedure andhomogeneity of magnetic field was optimized using adamantane sample(resulting line-width at half-height Δv_(1/2) was less than 3.5 Hz at250 ms of acquisition time). Taking into account frictional heating ofthe samples during fast rotation all NMR experiments were performed at305 K (precise temperature calibration was performed)

TABLE 3 Key parameters such as repetition delay, D1, and number ofscans, NS) for each of the measured samples D1,s NS T, K Palbociclibdimesylate, 4 s 500 305K Form E Palbociclib dimesylate, 4 s 808 305KForm F

Specific Surface Area (SSA) Method

SSA measurement based on BET-nitrogen adsorption were carried out usinga Micromeritics TriStar II Plus 3030 specific surface area analyzertogether with Micromeritics VacPrep 061 degassing station.

Setup:

Software version: Microactive for TriStar II Plus v 2.03

Adsorbate: Nitrogen

Sample tube: ½″ round bottom cell with glass filler rodsSample masses*: Approximately % full cellSample preparation: VacPrep 061, nitrogen streamOut gassing conditions: 16 hrs at 25° C. under vacuumIsothermal jacket: UsedIsothermal collection points: 11 point BET in the range 0.05-0.30 P/PoIsothermal data analysis range: 7 point BET in the range 0.05-0.20 P/PoLeak test: 120 sFree space: MeasuredEvacuation time: 1 hrOutgas test duration: 180 sEquilibration interval: 10 sEquilibration timeout: 600 sCalculations and Reporting: The specific surface area was reported inthe range 0.05-0.20 P/Po using 7 point BET from a triplicatedetermination.

EXAMPLES Example 1: Preparation of tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(Compound II)

tert-Butyl4-(6-(6-(1-butoxyvinyl)-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate(5.6 kg) was suspended in n-butanol (28 L), n-butyl-vinyl ether (6.72kg) and DIPEA (N,N-diisopropylethylamine) (2.18 L) were added, followedby a suspension of palladium acetate (43 g) and DPEPhos(bis[(2-diphenylphosphino)phenyl] ether), (206 g) in n-butanol (5.6 L).The mixture was heated at 80° C.

After reaction completion, water (0.84 L) was added and, after 45 minstirring at 80° C., the obtained solution was cooled and seeded (NBseeding step is optional). The suspension was cooled to 0° C. in 8 h andthen stirred at 0° C. for 4 h. Upon filtration, washing with n-butanol(5.6 L) and drying at 60° C. under vacuum, the title compound wasobtained (5.36 kg, 93% yield, 99.59% purity).

Example 2: Preparation of Palbociclib Dimesylate Form E

In a 500 ml reactor a mixture of water (34 ml, 2 v/w), acetone (51 ml, 3v/w) and methanesulfonic acid (5.5 ml) was heated at 65° C. Compound II(17 g, purity—99.67 A %, Impurity A1 content—0.12 A %) was addedportionwise in 90 min. The final suspension was cooled at 25° C., keptat this temperature for 16 h and then heated to reflux for 2 h, untilcomplete dissolution of the solid material. Keeping the reflux, acetone(272 ml, 16 v/w) was added over 20 min: the final suspension was kept atreflux for 30 min and then cooled at 25° C. in 15 min and kept at thistemperature for 16 h.

The suspension was filtered and washed with acetone. Upon drying in ovenat 40° C. under vacuum, the title compound was obtained (17.2 g, yield97.4%, purity 99.85 A %, Impurity A content—0.10 A %).

The product was analyzed by PXRD, indicating that Form E was obtained.The XRPD pattern is presented in FIG. 1.

Mesylate potentiometric titration: 29.9% (theoretical 30.0%)

NMR: DMSO; ¹H, 400 MHz

2.43, 2.49, 2.52, 3.38, 3.54, 7.82, 8.16, 9.14 ppm

Example 3: Preparation of Palbociclib Dimesylate Form F A. Procedure 1

In a 10 L reactor compound II (200 g, purity—99.59 A %, Impurity A1content—0.09 A %) was loaded, followed by water (800 ml, 4 v/w) andmethanesulfonic acid (95.5 g). The suspension was heated to 80° C. for 3h, until a cloudy solution was obtained. The mixture was cooled to 50°C. and filtered, then acetone (4000 ml, 20 v/w) was added. The finalsuspension was cooled to −3° C. at 10° C./h rate.

The suspension was filtered and washed with acetone. Upon drying in ovenat 40° C. under vacuum, the title compound was obtained (165 g, yield77.9%, 99.9 A %, Impurity A content <0.04 A %).

The product was analyzed by PXRD, indicating that Form F was obtained.The XRPD pattern is presented in FIG. 3.

NMR: D₂O, ¹H, 400 MHz

2.28, 2.39, 2.71, 3.39, 3.45, 7.37, 8.00, 8.90 ppm

B. Procedure 2

In a 1000 ml reactor compound II (31 g, purity—99.12 A %, Impurity A1content—0.26 A %) was suspended in acetone (93 ml, 3 v/w) and heated at50° C. A solution of methanesulfonic acid (10 ml, 3 eq) in water (62 ml,2 v/w on compound II) was added in 40 min. The suspension was kept at50° C. for 16 h till dissolution, then cooled to 25° C. Acetone (550 ml,17.7 v/w) was added over around 30 minutes keeping 25° C. and the finalsuspension was stirred at 25° C. for 1 h.

Upon filtration, washing with acetone and drying in oven at 40° C. undervacuum, the title compound was obtained (28.8 g, yield 105.3%, purity99.62 A %, Impurity A content—0.15 A %). The product was analyzed byPXRD, indicating that Form F was obtained.

C. Procedure 3

In a reactor compound II (4.58 kg) was charged, followed by water (18.3L). The mixture was stirred, while heating to 80° C. Once the targettemperature was reached, methanesulfonic acid (2.19 kg) was slowlyadded, (over 120 minutes) in order to control foaming. At the end of theaddition, the mixture was stirred at 80° C. for 1 h, then the resultingcloudy solution was filtered, washing lines and cartridge with water(2.5 L). Keeping the temperature around 50° C., acetone (109 L) wasadded (during 45 minutes). After addition, the reaction mixture wasstirred for 5 minutes to afford a clear solution and then cooled toaround 35° C. The resulting suspension was stirred for 2 hours, thencooled to −10±5° C. in about 5 h. Palbociclib Dimesylate suspension wasstirred at −5° C. for 8 h, then filtered and washed with acetone. Upondrying in oven at 25-30° C. under vacuum, Palbociclib dimesylate wasobtained as a yellowish solid (3.51 kg, 100% purity). The product wasanalyzed by PXRD, indicating that Form F was obtained.

Example 4: Preparation of Palbociclib Dimesylate Form G

In a 250 ml reactor, compound II (9 g) was suspended in water (86 ml 9.6v/w) and acetone (42 ml, 4.7 v/w) at 25° C., methanesulfonic acid (7.16g 5 eq) dissolved in a mixture of water (9 ml) and acetone (18 ml) wasadded and the mixture was heated at 50° C. for 5 h obtaining a cloudysolution.

After cooling at 25° C., the solution was filtered through a dicalitepad, then sodium hydroxide 10% water solution was added and the titlecompound precipitated off.

Upon filtration and washing with water and acetone, crude Palbociclibwas dried under vacuum at 40° C. for 16 h (5.6 g, yield 86%)

In a 100 ml reactor, the crude palbociclib (5 g) was suspended in water(20 ml, 4 v/w) and methanesulfonic acid (20 ml, 4 v/w, 37 eq). Themixture was heated at 55° C. for 1 h obtaining a clear solution.

In a 500 ml reactor acetone (300 ml, 60 v/w) was prepared and, keepingthe temperature at 25° C., the Palbociclib solution previously preparedwas added in 5 min.

The obtained suspension was stirred for 5 min and then filtered.

Upon washing with acetone and drying in oven at 40° C. under vacuum, thetitle compound was obtained (5.5 g, yield 105%). The product wasanalyzed by PXRD, indicating that Form G was obtained. The XRPD patternis presented in FIG. 4.

Example 5: Preparation of Palbociclib

Palbociclib dimesylate (30 g, obtained according to example 3,procedure 1) was suspended in water (468 ml) and acetone (292 ml) at 25°C., stirring until dissolution. Keeping the Palbociclib dimesylatesolution at 25° C., a solution of sodium hydroxide 10% in water wasadded until pH=11, causing the precipitation of Palbociclib.

The suspension was stirred for 1 h, then filtered and washed with waterand acetone. Upon drying in oven at 40° C. under vacuum, the titlecompound was obtained (18.3 g, yield 89%, purity 99.95%, Impurity Acontent<0.04%).

Example 6: Preparation of Palbociclib

Palbociclib dimesylate (3.51 kg) was suspended in water (40 L) andacetone (23 L). The suspension was stirred at 28° C. until dissolution.Aqueous sodium hydroxide (10% w/w) was added in 85 minutes, until pH=12,causing the precipitation of Palbociclib. The suspension was stirred for20 minutes, then filtered and washed with water and acetone. Upon dryingin oven at 45° C. under vacuum, the title compound was obtained (2.13kg, yield 92%, purity 100.0%, SSA 4.9 m²/g). The product was analyzed byPXRD, indicating that Form A was obtained.

1. A solid state form of Palbociclib dimesylate, selected from: (A) acrystalline form of Palbociclib dimesylate designated form E,characterized by data selected from one or more of the following: (i) anX-ray powder diffraction pattern having peaks at 9.2, 10.0, 16.4, 18.2and 21.9 degrees two theta±0.2 degrees two theta; (ii) an X-ray powderdiffraction pattern having peaks at 9.2, 10.0, 16.4, 18.2 and 21.9degrees two theta±0.2 degrees two theta and also having any one, two,three, four or five additional peaks selected from 6.0, 10.9, 12.7, 15.0and 15.6 degrees two theta±0.2 degrees two theta; (iii) an X-ray powderdiffraction pattern substantially as depicted in FIG. 1; (iv) an FT-IRspectrum having absorptions at 3385, 1697, 1607, 1529, 1332, 913, 857and 768 cm⁻¹±4 cm⁻¹; (v) an FT-IR spectrum substantially as depicted inFIG. 5; (vi) a solid state ¹³C NMR spectrum having peaks at 144.5,143.2, 131.5, 123.5 and 119.2 ppm±0.2 ppm; (vii) a solid state ¹³C NMRspectrum having the following chemical shift absolute differencesbetween said characteristic peaks at 144.5, 143.2, 131.5, 123.5 and119.2 ppm±0.2 ppm and a reference peak at 110.5 ppm±1 ppm of 34.0, 32.7,21.0, 13.0 and 8.7 ppm±0.1 ppm; or (viii) a solid state ¹³C NMR spectrumsubstantially as depicted in FIG. 7 or substantially as depicted in FIG.8; or (B) a crystalline form of Palbociclib dimesylate designated formF, characterized by data selected from one or more of the following: (i)an X-ray powder diffraction pattern having peaks at 6.7, 7.4, 9.4, 11.0and 18.8 degrees two theta±0.2 degrees two theta; (ii) an X-ray powderdiffraction pattern having peaks at 6.7, 7.4, 9.4, 11.0 and 18.8 degreestwo theta±0.2 degrees two theta and also having any one, two, three,four or five additional peaks selected from 8.0, 8.7, 13.5, 16.7 and17.8 degrees two theta±0.2 degrees two theta; (iii) an X-ray powderdiffraction pattern substantially as depicted in FIG. 3; (iv) an FT-IRspectrum having absorptions at 1701, 1655, 1619, 1583, 1541, 1210, 1041and 924 cm⁻¹±4 cm⁻¹; (v) an FT-IR spectrum substantially as depicted inFIG. 6; (vi) a solid state ¹³C NMR spectrum having peaks at 161.6,141.9, 141.1, 138.7 and 133.0 ppm±0.2 ppm; (vii) a solid state ¹³C NMRspectrum having the following chemical shift absolute differencesbetween said characteristic peaks at 161.6, 141.9, 141.1, 138.7 and133.0 ppm±0.2 ppm and a reference peak at 110.0 ppm±1 ppm of 51.6, 31.9,31.1, 28.7 and 23.0 ppm±0.1 ppm; or (viii) a solid state ¹³C NMRspectrum substantially as depicted in FIG. 9 or substantially asdepicted in FIG. 10; or (C) a crystalline form of Palbociclib dimesylatedesignated form G, characterized by data selected from one or more ofthe following: (i) an X-ray powder diffraction pattern having peaks at6.3, 7.2, 8.6, 9.3, 14.6, 16.4, 17.7 and 18.8 degrees two theta±0.2degrees two theta; or (ii) an X-ray powder diffraction patternsubstantially as depicted in FIG.
 4. 2. The crystalline form E accordingto claim 1(A), options (i), (ii), (iii), (iv), (v), (vi), (vii) or(viii) wherein the crystalline form is isolated, or wherein thecrystalline form is substantially free of any other solid state forms.3. The crystalline form F according to claim 1(B), options (i), (ii),(iii), (iv), (v), (vi), (vii) or (viii) wherein the crystalline form isisolated, or wherein the crystalline form is substantially free of anyother solid state forms.
 4. The crystalline form G according to claim1(C), options (i) or (ii) wherein the crystalline form is isolated, orwherein the crystalline form is substantially free of any other solidstate forms.
 5. A solid state form of Palbociclib dimesylate accordingto any one of claims 1-4 which contains: about 0.2% area percent orless, preferably 0.1% area percent or less, more preferably about 0.08%area percent or less, particularly 0.04% area percent or less ofImpurity A or Impurity A as a mesylate or dimesylate salt, as measuredby HPLC; or which contains: ≤1 wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %,≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt % (preferably ≤0.2 wt %, ≤0.1 wt % or≤0.05 wt %, and more preferably ≤0.1 wt % or ≤0.05 wt %) of Impurity Aor Impurity A as a mesylate or dimesylate salt.
 6. A solid state form ofPalbociclib dimesylate according to any one of claims 1-5, which has atotal impurity content of: not more than 0.4% area percent, preferablynot more than 0.3% area percent, more preferably not more than 0.2% areapercent, and particularly not more than 0.1% area percent, as measuredby HPLC; or which contains: ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt %or ≤0.05 wt % (preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and morepreferably ≤0.1 wt % or ≤0.05 wt %) of total impurities.
 7. Use of asolid state form of palbociclib dimesylate according to any one ofclaims 1-6 in the preparation of Palbociclib and or a salt thereof. 8.Use of a solid state form of palbociclib dimesylate according to any oneof claims 1-6 in the preparation of a pharmaceutical compositioncomprising palbociclib or a salt thereof.
 9. Use according to any one ofclaims 7-8 wherein the palbociclib or a salt thereof, or thepharmaceutical composition contains: about 0.2% area percent or less,preferably 0.1% area percent or less, more preferably about 0.08% areapercent or less, particularly 0.04% area percent or less of Impurity Aor a salt of Impurity A, as measured by HPLC; or wherein the palbociclibor a salt thereof, or the pharmaceutical composition contains: ≤1 wt %,≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %(preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1wt % or ≤0.05 wt %) of Impurity A, or a salt of Impurity A.
 10. Useaccording to any one of claim 7 or 9 wherein the palbociclib, or a saltthereof, contains: about 0.4% area percent or less, preferably 0.3% areapercent or less, more preferably about 0.2% area percent or less,particularly 0.1% area percent or less of total impurities, as measuredby HPLC; or wherein the palbociclib or salt thereof, contains: ≤1 wt %,≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %(preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1wt % or ≤0.05 wt %) of total impurities.
 11. A solid state form ofpalbociclib dimesylate according to any one of claims 1-6 for use in thepreparation of Palbociclib or a salt thereof.
 12. A solid state form ofpalbociclib dimesylate according to any one of claims 1-6 for thepreparation of a pharmaceutical composition comprising palbociclib or asalt thereof.
 13. A solid state form of palbociclib dimesylate accordingto any one of claims 11-12 for use in the preparation of palbociclib ora salt thereof or the pharmaceutical composition, wherein thepalbociclib or salt thereof or the pharmaceutical composition contains:about 0.2% area percent or less, preferably 0.1% area percent or less,more preferably about 0.08% area percent or less, particularly 0.04%area percent or less of Impurity A or a salt of Impurity A, as measuredby HPLC, or wherein the palbociclib or salt thereof contains: ≤1 wt %,≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %(preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1wt % or ≤0.05 wt %) of Impurity A or a salt of Impurity A.
 14. A solidstate form of palbociclib dimesylate according to any one of claim 11 or13, for use in the preparation of palbociclib or a salt thereof, whereinthe palbociclib or salt thereof contains: about 0.4% area percent orless, preferably 0.3% area percent or less, more preferably about 0.2%area percent or less, particularly 0.1% area percent or less of totalimpurities, as measured by HPLC or containing ≤1 wt %, ≤0.8 wt %, ≤0.5wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt % (preferably ≤0.2 wt%, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1 wt % or ≤0.05 wt %)of total impurities.
 15. A process for preparation of Palbociclib whichprocess comprises: a) providing the crystalline forms or a crystallineform according to any one of claims 1-6; b) converting palbociclibdimesylate to palbociclib; c) separating the solid palbociclib formed;and d) optionally washing and/or drying.
 16. A process according toclaim 15, wherein step a) comprises providing the crystalline forms or acrystalline form according to any one of claims 1-6 in a solution in apolar protic solvent or a polar aprotic solvent or a mixture thereof.17. The process according to claim 16 wherein the solution of thecrystalline forms or a crystalline form in step a) is in water and aketone (preferably a C₃-C₈ ketone), and preferably water and acetone.18. The process according any one of claims 15-17 wherein step b)comprises adding a base, preferably an inorganic base, more preferablyan alkali metal hydroxide, and most preferably wherein the base is NaOH.19. A process according to any of claims 15-18, comprising: a) providingthe crystalline forms or a crystalline form of Palbociclib dimesylateaccording to any one of claims 1-6 in a solvent system comprising apolar protic solvent or a polar aprotic solvent or a mixture thereof,preferably wherein the solvent system comprises water and a ketone(preferably a C₃-C₈ ketone) and preferably water and acetone andoptionally stirring until dissolution; b) adding a base, preferablyNaOH, optionally in the form of aqueous solution, to adjust the pH toabout 8 to about 14, preferably about 12; c) separating the solidpalbociclib formed and optionally washing; and d) optionally drying toobtain palbociclib.
 20. A process for the preparation of Palbociclibcomprising: (a) reacting tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(compound II) with methane sulfonic acid to form Palbociclib dimesylate,and (b) converting the Palbociclib dimesylate to Palbociclib.
 21. Aprocess according to claim 20 for the preparation of Palbociclib, whichprocess comprises: a) providing tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(compound II) and methanesulfonic acid in a solvent system comprisingone or more polar solvents, preferably wherein the solvent systemcomprises water, and heating the reaction mixture to a temperature offrom about 25° C. to about the reflux temperature of the solvent system;or providing tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(compound II) in a solvent system comprising one or more polar solvents,preferably wherein the solvent system comprises water, and heating thereaction mixture to a temperature of from about 25° C. to about thereflux temperature of the solvent and adding methanesulfonic acid; b)cooling the reaction mixture to a temperature lower than the temperatureof step a) but not less than about 0° C.; c) optionally filtering; d)adding a suitable anti solvent to afford a suspension; e) cooling thesuspension to a temperature of about 25° C. to about (−15) ° C.; f)filtering and optionally washing with the anti solvent used in step d)to isolate palbociclib dimesylate; and g) converting palbociclibdimesylate to palbociclib.
 22. A process according to claim 20 for thepreparation of Palbociclib, which process comprises: a) providingtert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(compound II) and methanesulfonic acid in a solvent system comprisingone or more polar solvents, preferably the solvent system compriseswater, and heating the reaction mixture to a temperature of from about25° C. to about the reflux temperature of the solvent system; orproviding tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(compound II) in a solvent system comprising one or more polar solvents,preferably the solvent system comprises water, and heating the reactionmixture to a temperature of from about 25° C. to about the refluxtemperature of the solvent and adding methanesulfonic acid; b)optionally cooling the reaction mixture to a temperature lower than thetemperature of step a but not less than about 0° C.; c) optionallyfiltering; d) adding a suitable anti solvent at a temperature of about25° C. to about reflux temperature, preferably at a temp of about 50°C.; e) optionally heating to reflux temperature; f) cooling the reactionmixture to a temperature of about 25° C. to about (−15) ° C.; g)separating the solid palbociclib dimesylate and optionally washing withthe anti solvent used in step d); and h) converting palbociclibdimesylate to palbociclib.
 23. A process according to any one of claims21-22 wherein the reaction mixture in step a) is heated to a temperatureof from: about 40° C. to about 95° C., about 50-90° C., about 70 toabout 90° C. or about 80° C.
 24. A process according to any one ofclaims 21-23 wherein the solvent system in step a) consists essentiallyof water, preferably wherein the solvent system contains 90% or more,preferably 95% or more, or more preferably 98% or more water.
 25. Aprocess according to any one of claims 21, 23-24 wherein step c) isperformed prior to step b).
 26. The process according to any one ofclaims 22-24, wherein step d) is performed prior to step c).
 27. Aprocess according to any one of claims 21-26 wherein the anti solvent isselected from a group consisting of ketones (preferably a C₃-C₈ ketone),esters (preferably a C₃-C₈ ester) and alcohol (preferably C₁-C₆alcohol).
 28. A process according to any one of claims 21-27 wherein theamount of anti solvent added is such that it results in a solventmixture wherein the ratio of anti-solvent to solvent is at least about2:1 (v/v), preferably at least about 3:1 (v/v), more preferably at leastabout 4:1 (v/v), or wherein the ratio of anti-solvent to solvent is fromabout: 2:1 to about 25:1, about 2:1 to about 20:1, about 3:1 to about25:1, about 3:1 to about 20:1, about 3:1 to about 15:1, about 4:1 toabout 25:1, about 4:1 to about 20:1, about 4:1 to about 15:1, or about4:1.
 29. A process according to any one of claims 21-28 wherein theanti-solvent is a ketone, (preferably a C₃-C₈ ketone), preferablyacetone.
 30. A process according to claim 20, for the preparation ofPalbociclib, which process comprises: a) providing tert-Butyl4-[6-[[6-(1-Butoxyethenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]amino]-pyridin-3-yl]-piperazine-1-carboxylate(compound II) in a solvent system comprising water, and heating thereaction mixture to a temperature of about 80° C.; b) addingmethanesulfonic acid; c) optionally cooling the reaction mixture to atemperature lower than the temperature of step a) but not less thanabout 0° C., preferably to about 50° C.; d) optionally filtering; e)adding acetone at a temperature of about 25° C. to about refluxtemperature, preferably at a temp of about 50° C.; f) optionally heatingto reflux temperature to obtain a solution; g) cooling the reactionmixture to a temperature of about 25° C. to about (−15) ° C., morepreferably about 0° C. to about (−10) ° C.; h) separating the solidpalbociclib dimesylate and optionally washing with the acetone; and i)converting palbociclib dimesylate to palbociclib.
 31. The processaccording to claim 21-30 wherein the solvent system in step a) consistsessentially of water, preferably wherein the solvent system contains 90%or more, preferably 95% or more, or more preferably 98% or more water.32. The process according to any one of claims 30-31 wherein thesolvents in the reaction mixture in step e) consist essentially ofacetone and water wherein the ratio of acetone to water is at leastabout 4 volumes of acetone per one volume of water.
 33. The processaccording to any one of claims 30-32 wherein in step g) the reactionmixture is cooled to a temperature of about (−5) ° C.
 34. The processaccording to any one of claims 20-33 wherein the step of convertingpalbociclib dimesylate to palbociclib comprises the following steps: A)providing palbociclib dimesylate in a solvent system comprising a polarprotic solvent or a polar aprotic solvent or a mixture thereof,preferably wherein the solvent system comprises water and acetone, andoptionally stirring until dissolution; B) adding a base, preferablyNaOH, optionally in the form of aqueous solution, to adjust the pH toabout 8 to about 14, preferably about 12; C) separating the solidpalbociclib formed and optionally washing; and D) optionally drying. 35.A process according to any of claims 15-34, wherein the Palbociclibcontains: 0.2% area percent or less, preferably 0.1% area percent orless, more preferably 0.08% area percent or less, particularly 0.04%area percent or less, of Impurity A or a salt of Impurity A, as measuredby HPLC or wherein the content of impurity A is: ≤1 wt %, ≤0.8 wt %,≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt % (preferably≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1 wt % or≤0.05 wt %).
 36. A process according to any of claims 15-35, wherein thepalbociclib contains: about 0.4% area percent or less, preferably 0.3%area percent or less, more preferably about 0.2% area percent or less,particularly 0.1% area percent or less of total impurities, as measuredby HPLC, or wherein the palbociclib contains: ≤1 wt %, ≤0.8 wt %, ≤0.5wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt % (preferably ≤0.2 wt%, ≤0.1 wt % or ≤0.05 wt %, and more preferably ≤0.1 wt % or ≤0.05 wt %of total impurities.
 37. A process according to any of claims 15-36,further comprising combining the Palbociclib with at least onepharmaceutically acceptable excipient to form a pharmaceuticalcomposition.
 38. Palbociclib wherein the content of Impurity A is: 0.2%area percent or less, preferably 0.1% area percent or less, morepreferably 0.08% area percent or less, particularly 0.04% area percentor less, as measured by HPLC, or wherein the content of impurity A is:≤1 wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25 wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05wt % (preferably ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt %, and more preferably≤0.1 wt % or ≤0.05 wt %) of Impurity A, or wherein the palbociclibcontains: about 0.4% area percent or less, preferably 0.3% area percentor less, more preferably about 0.2% area percent or less, particularly0.1% area percent or less of total impurities, as measured by HPLC, orwherein the palbociclib contains: ≤1 wt %, ≤0.8 wt %, ≤0.5 wt %, ≤0.25wt %, ≤0.2 wt %, ≤0.1 wt % or ≤0.05 wt % (preferably ≤0.2 wt %, ≤0.1 wt% or ≤0.05 wt %, and more preferably ≤0.1 wt % or ≤0.05 wt %) of totalimpurities, which is produced by the process according to any one ofclaims 15-36.
 39. A pharmaceutical composition comprising palbociclibaccording to claim
 38. 40. A process for preparation of a pharmaceuticalcomposition according to claim 39 comprising combining the Palbociclibaccording to claim 38 with at least one pharmaceutically acceptableexcipient.
 41. Palbociclib according to claim 38 or the pharmaceuticalcomposition according to claim 39 for use in therapy.
 42. Palbociclibaccording to claim 38 or the pharmaceutical composition according toclaim 39 for use in the treatment of cancer.
 43. Use of palbociclibaccording to claim 38 in the preparation of a medicament for thetreatment of cancer.
 44. A method of treating cancer comprisingadministering a therapeutically effective amount of pharmaceuticalcomposition according to claim
 39. 45. A pharmaceutical compositioncomprising a solid state form of palbociclib dimesylate according to anyone of claims 1-6.
 46. A process for preparation of a pharmaceuticalcomposition according to claim 45 comprising combining the solid formsof Palbociclib dimesylate according to any one of claims 1-6 with atleast one pharmaceutically acceptable excipient.
 47. The crystallineforms of palbociclib dimesylate according to any one of claims 1-6 orthe pharmaceutical composition according to claim 45 for use in therapy.48. The crystalline forms of palbociclib dimesylate according to any oneof claims 1-6 or the pharmaceutical composition according to claim 45for use in the treatment of cancer.
 49. Use of the crystalline forms ofPalbociclib dimesylate according to any one of claims 1-6 in thepreparation of a medicament for the treatment of cancer.
 50. A method oftreating cancer comprising administering a therapeutically effectiveamount of pharmaceutical composition according to claim 45.